Aryl substituted aminomethyl benzene derivatives

ABSTRACT

The present invention relates to new compounds of the formula ##STR1## wherein X is ##STR2## wherein R 1  is hydrogen, lower alkyl, phenyl, benzyl, cinnamoyl, thiophene, furan, pyrrole, imidazole, pyrazole oxazole or thiazole; W is hydrogen or hydroxy; (Y) A  is positioned ortho to W and is an aminoloweralkyl having the formula --CH 2  NR 2  R 3  where R 2  and R 3  are the same or different and may be lower alkyl or R 2  and R 3  may together with N form a pyrrolidine, piperidine or azepine ring, and A is 2; n and m are independently from 0 to 5; and R is straight or branched C 1  -C 10  alkyl, straight or branched C 3  -C 10  cycloalkyl, straight or branched C 2  -C 4  alkenyl or straight or branched C 2  -C 4  alkynyl, or a pharmaceutically acceptable salt thereof. 
     These compounds are useful in the treatment of various cardiac arrhythmias.

This application is a division of application Ser. No. 813,734, filed12/27/85, now U.S. Pat. No. 4,798,184.

BACKGROUND OF THE INVENTION

Cardiac arrhythmias represent a clinically significant disorder of thenormal rhythm of the heart and usually require immediate and specifictherapy. A common cause of cardiac arrhythmias is coronary arterydisease, where a high incidence of arrhythmias has been observed duringacute myocardial infarction. Premature ventricular contractions andsinus tachycardia are among the two most common types of arrhythmiasassociated with myocardial infarction. Although these and other types ofarrhythmias can be suppressed by the use of antiarrhythmic agents, theprevention of the recurrence of tachyarrhythmias is often necessary forlong periods of time or even indefinitely. Consequently, theseantiarrhythmic drugs must not only be effective and reliable, but theymust have a minimal number of adverse side-effects associated therewith.

The heart is endowed with a specialized excitatory system for generatingrhythmical impulses that cause rhythmical contraction of the heartmuscle and conductive system for conducting these impulses throughoutthe heart. A major portion of cardiac disorders is based onabnormalities of this specialized excitatory and conductive systemresulting in irregular sinus rhythm. Cardiac arrhythmias as describedabove, and in particular tachyarrhythmias, are caused by disorders ofelectrical impulse formation, by disturbances in impulse conduction, orby a combination of the two. Drugs used to treat tachyarrhythmiasgenerally reduce or suppress excitation of the heart muscle bydepressing spontaneous diastolic depolarization, and affect conductionby altering the conduction velocity through the myocardial tissue andthe duration of the refractory period.

Antiarrhythmic drugs are generally administered on a long-term basis tomaintain normal sinus rhythm after electrical cardioversion after normalcardiac action has been restored as alluded to above. Quinidine,6-methoxy-α-(5'-vinyl-2-quinuclidinyl)-4-quindinemethanol anddisopyramide, α[2-(diisopropylamino)-ethyl]α-phenol-2-pyridine-acetamideare two antiarrhythmic agents which depress impulse formation, slowconduction velocity, and increase the duration of the refractory periodof cardiac cells; and thus are useful in the treatment ofsupraventricular and ventricular tachyarrhythmias. However, in additionto the direct effect on the cardiac rhythm, both of these agents exhibitindirect anticholinergic actions which may affect the vagal stimulationof the heart and have an affect on peripheral parasympatheticstimulation.

Both quinidine and disopyramide exhibit adverse side-effects whenadministered to patients for the management of arrhythmias. Theside-effects associated with quinidine include, inter alia,cardiotoxicity, diarrhea, nausea, vomiting, fever, hypertension anddepression of myocardial contractility. Likewise, the side effectsassociated with associated with disopyramide include, inter alia,dryness of the mouth, blurred vision, constipation, and urinaryretention, and depression of myocardial contractility.

Changrolin,4-[3',5'-bis[N-pyrolidinylmethyl]-4'-hydroxyanilino]-quinazoline, aneffective antiarrhythmic agent, also possesses substantialanticholinergic activity together with the ability to cause skindiscoloration in some patients.

Heretofore, there has not been an effective antiarrhythmic agentavailable that has not been plagued by one or more of these unwanted,adverse side-effects, many of which are caused by excessiveanticholinergic activity. In accordance with the present invention,disclosed are compounds having effective antiarrhythmic activity withless of the unwanted anticholinergic activity associated with theseantiarrhythmic drugs.

SUMMARY OF THE INVENTION

In accordance with the present invention, disclosed herein are compoundsof the formula ##STR3## wherein x is ##STR4## lower straight chainedalkylene, or --S-- wherein R₁ is hydrogen, aryl, or lower alkyl; W ishydrogen, hydroxy, amino, ##STR5## -O-alkyl, alkylsulfonamido or-O-aralkyl; (Y)_(A) is positioned ortho to W and is an aminoalkyl havingthe formula --CH₂ NR₂ R₃, wherein R₂ and R₃ may together with N form a5- to 7-membered heterocyclic group optionally including oxygen,nitrogen, or sulfur as a second heteroatom, and A is 1 or 2 with theproviso that when A is 1 that W is hydroxy, amino, ##STR6## -O-alkyl, or-O-aralkyl; N and M are independently from 0 to about 5; and R isstraight or branched C₁ -C₁₀ alkyl, C₃ -C₁₀ cycloalkyl, straight orbranched C₂ -C₄ alkenyl, or straight or branched C₂ -C₄ alkynyl.

BRIEF DESCRIPTION OF THE INVENTION

The compounds in accordance with the present invention are structurallygenerally characterized by an aromatic region coupled through a linkageregion as shown below ##STR7## The aromatic region ##STR8## includes apara-substituted phenyl group having one or two alkyl- orarylaminomethyl substituents positioned adjacent (ortho) thereto. Thepara-substituent W may be hydrogen, hydroxy, amino, ##STR9## -O-alkyl,alkylsulfonamido or -O-aralkyl when A is 2; and hydroxy, amino,##STR10## -O-alkyl, or -O-aralkyl when A is 1. Preferably W is hydroxy,amino, ##STR11## -O-alkyl, or -O-aralkyl when A is either 1 or 2.Illustrative of W subsitutents having the formula ##STR12## are thoseincluding but not limited to lower acyloxy groups such as acetoxy,propionyloxy, butyryloxy, and aroyloxy groups such as benzoyloxy, andthe like. Illustrative of W substituents having the formula -O-alkyl or-O-aralkyl are those including but not limited to lower alkyloxy andaralkyloxy groups such as methoxy, ethoxy, propoxy, butoxy, benzyloxy,phenethyloxy, phenepropyloxy, and the like. In accordance with thepresent invention, we have advantageously found para-hydroxysubstituents effective as antiarrhythmics; thus W is most preferablyhydroxy.

The alkyl or arylaminomethyl substituents of the present invention arerepresented by the general formula --CH₂ NR₂ R₃, where R₂ and R₃ are thesame or different and may be hydrogen, lower alkyl, hydroxyalkyl such ashydroxylated straight or branched chain lower alkyl radicals,cycloalkyl, aryl, alkoxy, aralkoxy, alkoxyaryl, or heteroaryl. In thecase where R₂ and R₃ are both hydrogen, it may be necessary to employconventional blocking reagents to the amine during preparation of thesecompounds which are removed after the coupling of the amino substituentsas set forth below. Moreover, R₂ and R₃ cannot both be alkoxy sincecompounds of this type would be unstable. Illustrative of alkyl-orarylaminomethyl substituents having the formula --CH₂ NR₂ R₃ are thoseincluding but not limited to those where R₂ and R₃ are methyl, ethyl,propyl, butyl, ethanol, 2-propanol, 3-propanol, butanol, methoxy,ethoxy, phenoxy, benzyloxy, cyclopentyl, cyclohexyl, cycloheptyl,phenyl, benzyl, thiophene, furan, pyrole, pyran, thiophan, pyrrolidine,piperidine, morpholine, piperazine, thiomorpholine, and thioxane.Preferred alkylaminomethyl substituents in accordance with the presentinvention are dimethylaminomethyl.

Alternatively, R₂ and R₃ may together with N form a 5 to 7 memberedsaturated or unsaturated heterocyclic group optionally including oxygen,nitrogen, or sulfur as a second heteroatom, each which may besubstituted or unsubstituted. Illustrative of heterocyclic groups formedwith N are those including but not limited to pyrrolidine, piperidine,morpholine, pyridine, pyrrole, piperazine, thiomorpholine, and the like.In accordance with one embodiment of the present invention, we haveadvantageously found alkylaminomethyl substituents where R₂ and R₃ formheterocycles with N such as pyrrolidine, piperidine, and morpholineeffective as antiarrhythmics and are thus the preferred. The mostpreferred heterocyclic aminomethyl substituent is pyrrolidine. Inaccordance with the present invention, we have found thatbis-aminomethyl (A=2) substituted compounds have effectiveantiarrhythmic activity and are most preferred.

In accordance with a preferred embodiment of the present invention,effective antiarrhythmic compounds can be made which lack a parahydroxylsubstituent (W) and thus will lack in part the ability for extendedconjugation of the phenol through the aryl group (Ar). We contemplatethat skin discoloration associated with changrolin is due to theoxidation of the aminophenol moiety to a quinone-like structure whichcould result in the formation of a strong chromophore which is depositedin the skin. Thus, in accordance with one embodiment of the presentinvention, the W substituent should be incapable of forming such achromophore, and is preferably hydrogen. Preferably, when W is hydrogen,the aromatic group is bis-aminomethyl (A=2).

Another region of interest is the covalent linkage --(CH₂)_(N)--(X)--(CH₂)_(M) -- between the aromatic groups. In accordance with thepresent invention, this linkage has been found to tolerate modificationwithout significant loss of pharmacological activity, and in particularantiarrhythmic potency. Linkage portions in accordance with the presentinvention may be those where x is ##STR13## lower straight chainedalkylene, or sulfur, where R₁ is hydrogen, lower alkyl, or aryl such asphenyl, substituted phenyl, benzyl, substituted benzyl, or heteroaryls.Preferably, x is ##STR14## or -O-where R₁ preferably is hydrogen orlower alkyl with hydrogen being most preferred. More preferred inaccordance with the present invention are linkages where x is ##STR15##where R₁ is hydrogen or lower alkyl with hydrogen being most preferred.The most preferred linkages in accordance with the present invention iswhere x are ##STR16##

The alkylene groups in the linkage portion of these compounds mayindependently have from 0 to about 5 carbon atoms, and are preferablyfrom 0 to about 2. More preferably, the linkage is such that M+N is 0,1, or 2; and is most preferable where M+N is 0 or 1 such that M iseither 0 or 1 and N is 0. Thus, illustrative linkage portions having theformula

    --(CH.sub.2).sub.N --X--(CH.sub.2).sub.M --

are those including but not limited to X, --CH₂ X--, --XCH₂ --, --CH₂CH₂ X--, --CH₂ XCH₂ --, --XCH₂ CH₂ ; such as ##STR17## and the like.

In accordance with one embodiment of the present invention effectiveantiarrhythmic compounds can be made having linkage regions which lackthe ability for extended conjugation from the para-hydroxy substituentto the aryl group (Ar) as discussed above. One way of eliminating thisconjugation is through the insertion of methylenes between X and theaminomethyl substituted phenolic group such that --(CH₂)_(M) -- is notzero; and another way is to replace X such that extended conjugation isnot possible. For example, when X is ##STR18## the ability for extendedconjugation is reduced.

Illustrative preferred compounds in accordance with the presentinvention include, but are not limited to, those represented by the listbelow where W is hydroxy; (Y)_(A) is independently and preferablypyrrolidinylmethyl, piperidinylmethyl or morpholinomethyl; A is 2; H₁ isoxygen, nitrogen, or sulfur; Z is hydrogen or other substituent; *N a6-membered heteroaryl containing 1 or 2 nitrogen atoms; and the aryl isbonded to the linkage portion at positions indicated by either a solidor dotted line:

    __________________________________________________________________________    Aryl          (CH.sub.2).sub.N                                                                     X      (CH.sub.2).sub.M                                  __________________________________________________________________________     ##STR19##    N = 0 or 1                                                                            ##STR20##                                                                           M = 0, 1, or 2                                     ##STR21##    N = 0 or 1                                                                            ##STR22##                                                                           M = 0, 1, or 2                                     ##STR23##    N = 0 or 1                                                                            ##STR24##                                                                           M = 0, 1, or 2                                     ##STR25##    N = 0 or 1                                                                            ##STR26##                                                                           M = 0, 1, or 2                                     ##STR27##    N = 0 or 1                                                                            ##STR28##                                                                           M = 0, 1, or 2                                     ##STR29##    N = 0 or 1                                                                            ##STR30##                                                                           M = 0, 1 or 2                                      ##STR31##    N = 0 or 1                                                                            ##STR32##                                                                           M = 0, 1 or 2                                      ##STR33##    N = 0 or 1                                                                            ##STR34##                                                                           M = 0, 1, or 2                                     ##STR35##    N = 0 or 1                                                                            ##STR36##                                                                           M = 0, 1, or 2                                     ##STR37##    N = 0 or 1                                                                            ##STR38##                                                                           M = 0, 1, or 2                                     ##STR39##    N = 0 or 1                                                                            ##STR40##                                                                           M = 0, 1, or 2                                     ##STR41##    N = 0 or 1                                                                            ##STR42##                                                                           M = 0, 1, or 2                                     ##STR43##    N = 0 or 1                                                                            ##STR44##                                                                           M = 0, 1, or 2                                     ##STR45##    N = 0 or 1                                                                            ##STR46##                                                                           M = 0, 1, or 2                                     ##STR47##    N = 0 or 1                                                                            ##STR48##                                                                           M = 0, 1, or 2                                     ##STR49##    N = 0 or 1                                                                            ##STR50##                                                                           M =  0, 1, or 2                                    ##STR51##    N = 0 or 1                                                                            ##STR52##                                                                           M = 0, 1, or 2                                     ##STR53##    N = 0 or 1                                                                            ##STR54##                                                                           M = 0, 1, or 2                                     ##STR55##    N = 0 or 1                                                                            ##STR56##                                               M = 0, 1, or 2                                                                 ##STR57##    N = 0 or 1                                                                            ##STR58##                                               M = 0, 1, or 2                                                                 ##STR59##    N = 0 or 1                                                                            ##STR60##                                                                           M = 0, 1, or 2                                     ##STR61##    N = 0 or 1                                                                            ##STR62##                                                                           M = 0, 1, or 2                                     ##STR63##    N = 0 or 1                                                                            ##STR64##                                                                           M = 0, 1, or 2                                     ##STR65##    N = 0 or 1                                                                            ##STR66##                                                                           M = 0, 1, or 2                                     ##STR67##    N = 0 or 1                                                                            ##STR68##                                                                           M = 0, 1, or 2                                     ##STR69##    N = 0 or 1                                                                            ##STR70##                                                                           M = 0, 1, or 2                                     ##STR71##    N = 0 or 1                                                                            ##STR72##                                                                           M = 0, 1, or 2                                     ##STR73##    N = 0 or 1                                                                            ##STR74##                                                                           M = 0, 1, or 2                                     ##STR75##    N = 0 or 1                                                                            ##STR76##                                                                           M = 0, 1, or 2                                     ##STR77##    N = 0 or 1                                                                            ##STR78##                                                                           M = 0, 1, or 2                                     ##STR79##    N = 0 or 1                                                                            ##STR80##                                                                           M = 0, 1, or 2                                     ##STR81##    N = 0 or 1                                                                            ##STR82##                                                                           M = 0, 1, or 2                                     ##STR83##    N = 0 or 1                                                                            ##STR84##                                                                           M = 0, 1, or 2                                     ##STR85##    N = 0 or 1                                                                            ##STR86##                                                                           M = 0, 1, or 2                                     ##STR87##    N = 0 or 1                                                                            ##STR88##                                                                           M = 0, 1, or 2                                     ##STR89##    N = 0 or 1                                                                            ##STR90##                                                                           M = 0, 1, or 2                                     ##STR91##    N = 0 or 1                                                                            ##STR92##                                                                           M = 0, 1, or 2                                     ##STR93##    N = 0 or 1                                                                            ##STR94##                                                                           M = 0, 1, or 2                                     ##STR95##    N = 0 or 1                                                                            ##STR96##                                                                           M = 0, 1, or 2                                     ##STR97##    N = 0 or 1                                                                            ##STR98##                                                                           M = 0, 1, or 2                                     ##STR99##    N = 0 or 1                                                                            ##STR100##                                                                          M = 0, 1, or 2                                     ##STR101##   N = 0 or 1                                                                            ##STR102##                                                                          M = 0, 1, or 2                                     ##STR103##   N = 0 or 1                                                                            ##STR104##                                                                          M = 0, 1, or 2                                     ##STR105##   N = 0 or 1                                                                            ##STR106##                                                                          M = 0, 1, or 2                                     ##STR107##   N = 0 or 1                                                                            ##STR108##                                                                          M =  0, 1, or 2                                    ##STR109##   N = 0 or 1                                                                            ##STR110##                                                                          M = 0, 1, or 2                                     ##STR111##   N = 0 or 1                                                                            ##STR112##                                                                          M = 0, 1, or 2                                     ##STR113##   N = 0 or 1                                                                            ##STR114##                                                                          M = 0, 1, or 2                                     ##STR115##   N = 0 or 1                                                                            ##STR116##                                                                          M = 0, 1, or 2                                     ##STR117##   N = 0 or 1                                                                            ##STR118##                                                                          M = 0, 1, or 2                                    __________________________________________________________________________

The compounds of the present invention and equivalents thereofpossessing substantially similar pharmacological property may beprepared according to several general schemes as set forth below.

SCHEME I

The arylamide derivatives of the substituted aminophenols are preparedby aminomethylation of acetominophen by the Mannich reaction, removingthe acetyl group and reacting the aniline derivative with theappropriate aromatic acid chloride. ##STR119##

SCHEME III

The aryloxy derivatives of the substituted aminophenols are prepared byaminomethylation of the appropriate p-aryloxyphenol. ##STR120##

SCHEME IV

The keto derivatives of the substituted phenols are prepared byaminomethylation of the appropriate p-hydroxybenzo-aryl ketone.##STR121##

SCHEME V

Aryl amide derivatives of the substituted phenols are prepared bydemethylation of p-methoxybenzylamine followed by reaction with theappropriate aromatic acid chloride and aminomethylation. ##STR122##

The mono-substituted aminoalkyl compounds in accordance with the presentinvention are co-produced with the di-substituted compounds and areseparated therefrom by medium pressure liquid chromatography (MPLC) onsilica gel columns.

The compounds of the present invention possess advantageouspharmacological properties useful for the treatment of cardiacarrhythmias, and in particular for the suppression of supraventricularand ventricular tachyarrthmias. It is contemplated that these compounds,in addition to maintaining normal sinus rhythm by suppression oftachyarrhythmia, will be most useful prophylactically for the preventionof premature ventricular complex formation in human patients onlong-term therapy. Further, in accordance with one embodiment of thepresent invention, we have found that these compounds effectivelysuppress ventricular arrhythmias when administered orally orparenterally by infusion to dogs, while unexpectedly exhibiting abenefically low anticholinergic activity in guinea pig illeum tests.These compounds also exhibit superior antiarrhythmic properties to otherknown antiarrhythmic agents. Thus, the desirable antiarrhythmic potencyof these compounds is maximized in relationship to the undesirableside-effects associated with anticholinergic activity. Moreover, we havefound a low negative inotropic activity associated with compounds inaccordance with one embodiment of the present invention, whichadvantageously and unexpectedly reduces the incidence of acardiodepressant effect on the heart. Compounds lacking this adverseeffect on the heart would less likely cause cardiac failure. It isfurther contemplated that these compounds can be used as antimalarials.

The compounds in accordance with the present invention are madepharmacologically compatible, for example, by the neutralization of thefree amine groups thereof with non-toxic pharmaceutically acceptableinorganic or organic salts by conventional methods. Pharmaceuticallyacceptable salts of these compounds are illustrated by those includingbut not limited to hydrochloric acid, sulfuric acid, phosphoric acid,hydrobromic acid, acetic acid, lactic acid, citric acid, oxalic acid,malic acid, salicylic acid, and the like. Further, the pharmaceuticallyacceptable salts of compounds in accordance with the present inventionmay be used in admixture with a conventional solid or liquidpharmaceutical carrier or diluent. These compositions may beadministered orally or parentally by conventional methods. For oraladministration, fine powders or granules of the compound may containdiluents, binders, lubricants, and dispersing and surface active agents,and and the like may be in the dried state in coated or uncoatedtablets, or in suspension. For parenteral administration, the compoundsmay be in aqueous injection or infusion solutions which may containantioxidants, buffers, bacteriostats, solubilizing agents, and the likeor solutes which render the salts isotonic with the blood such as inisotonic saline.

The dosage of the novel compounds of the present invention depends onseveral factors, as determined for conventional antiarrhythmic agents.Dosages ranging from about 1 to about 20 mg per kg of body weight werefound to be effective in adult mongrel dogs (10-65 kg) when infusedintravenously at a cumulative rate of 0.3 mg/kg/min. Moreover, oraldosages ranging from about 20 to about 40 mg per kg of body weight havebeen found effective in these dogs.

The following examples are intended to be illustrative of the presentinvention but should not be considered as limiting the scope thereof:

EXAMPLE I 4-benzyloxy-2,6-bis(pyrrolidinylmethyl)phenol

This example describes the synthesis of a compound having the formula##STR123## A mixture of 5 g of p-benzyloxyphenol, 6.5 ml of a 37%solution of formaldehyde, and 4.5 ml of pyrrolidine in 3 ml of ethanolwas stirred with warming for 3 hours. The solvent was removed on arotary evaporator, the product was dissolved in CHCl₃, the solution waswashed with water, dried (MgSO₄) and saturated with dry hydrogenchloride affording an oil. Flash column chromatography (CHCl₃ /MeOH/NH₄OH; 9:2:0.1) again afforded an oil. The HCl salt was crystallized fromi-PrOH/EtOAc, yielding white crystals: mp 139°-141° C. The IR and NMRspectra were consistent with the assigned structure and the elementalanalysis was consistent with the empirical formula (C₂₃ H₃₀ N₂O₂.2HCl.0.5H₂ O).

EXAMPLE II 4-hydroxy-3,5-bis(pyrrolidinylmethyl)benzophenone

This example describes the synthesis of a compound having the formula##STR124## A mixture of 5 g of p-hydroxybenzophenone, 6.5 ml of a 37%solution of formaldehyde, and 4.5 ml of pyrrolidine in 3 ml of ethanolwas stirred with warming for 3 hours. The solvent was removed on arotary evaporator, the product was dissolved in CHCl₃, the solution waswashed with water, dried (MgSO₄) and saturated with dry hydrogenchloride affording an oil. Flash column chromatography (CHCl₃ /MeOH/NH₄OH; 9:2:0.05) again yielded an oil. The HCl salt was crystallized fromMeOH/EtOAc giving white crystals: mp 211°-212° C. The NMR spectra wereconsistent with the assigned structure and the elemental analysis wasconsistent with the empirical formula (C₂₃ H₂₈ N₂ O₂.2HCl).

EXAMPLES III-XVIII EXAMPLE IIIN-benzoyl-3,5-bis(N-pyrrolidinylmethyl)-4-hydroxyaniline

This example describes the synthesis of a compound having the formula##STR125## A mixture of 4 grams 4-acetamidophenol, 6.4 ml of a 37%solution of formaldehyde and 4.5 ml of pyrrolidine in 3 ml of ethanolwas stirred with warming for 3 hours. The solvent was removed on arotary evaporator, dissolved in CHCl₃, washed with water, dried (MgSO₄)and saturated with dry hydrogen chloride. The solvent was removed andcrystallization was effected with isopropanol/ether yielding whitecrystals.

A solution of 100.0 g (0.315 mol) of these crystals in 200 ml of 6M HClwas heated to reflux for 3 hours. The solution was basified with solidKOH to a pH of 11. The resulting solid was collected by filtration andwashed with water and cold ether. Crystallization from ether yieldedpale yellow needles.

A solution having equimolar amounts of these pale yellow crystals,benzoyl chloride, and triethylamine in dioxane was stirred for 6 hours.After the solvent was removed, the products was taken up in CHCl₃,washed with water, dried (MgSO₄), and the solvent removed. The oilafforded by this procedure was purified by MPLC (EtOAc/MeOH/NH₄ OH;9:1:0.05) and crystallized from EtOAC: mp 160°-161° C. The IR and NMRspectra were consistent with the assigned structure and the elementalanalysis was consistent with the empirical formula (C₂₃ H₂₉ N₃ O₂).

The additional compounds in Table I were prepared as above with theexception that the following aroyl chlorides were substituted forbenzoyl chloride. The IR and NMR spectra of each compound in Table Iwere consistent with the assigned structure and the elemental analysiswere consistent with the empirical formulae.

                                      TABLE I                                     __________________________________________________________________________    Example                                                                            Aroyl Chloride                                                                              M.P. (°C.)                                                                   Empirical Formula                                    __________________________________________________________________________    IV                                                                                  ##STR126##   133-135                                                                             C.sub.23 H.sub.28 N.sub.3 O.sub.2 Cl                       ##STR127##   50-55 C.sub.24 H.sub.31 N.sub.3 O.sub.2.0.5H.sub.2 O       VI                                                                                  ##STR128##   118-120                                                                             C.sub.23 H.sub.27 N.sub.3 O.sub.2 Cl.sub.2.2HCl.2                             H.sub.2 O                                            VII                                                                                 ##STR129##   158-159                                                                             C.sub.23 H.sub.28 N.sub.4 O.sub.4                    VIII                                                                                ##STR130##   55-57 C.sub.24 H.sub.31 N.sub.3 O.sub.3                    IX                                                                                  ##STR131##   90-93 C.sub.24 H.sub.28 N.sub.3 O.sub.2 F.sub.3.HCl.H.s                             ub.2 O                                               X                                                                                   ##STR132##   139-149                                                                             C.sub.23 H.sub.28 N.sub.3 O.sub.2 Cl                 XI                                                                                  ##STR133##   79-83 C.sub.23 H.sub.28 N.sub.3 O.sub.2 Cl.2HCl.H.sub.2                              O                                                   XII                                                                                 ##STR134##   113-115                                                                             C.sub.24 H.sub.28 N.sub.3 O.sub.2 F.sub.3.2HCl.1.                             5H.sub.2 O                                           XIII                                                                                ##STR135##   165-166                                                                             C.sub.24 H.sub.28 N.sub.3 O.sub.2 F.sub.3            XIV                                                                                 ##STR136##   233-235                                                                             C.sub.24 H.sub.31 N.sub.3 O.sub.3.2HCl               XV                                                                                  ##STR137##   69    C.sub.24 H.sub.31 N.sub.3 O.sub.2.2HCl.0.125H.sub                             .2 O                                                 XVI                                                                                 ##STR138##   204-205                                                                             C.sub.24 H.sub.31 N.sub.3 O.sub.2.2HCl.1.5H.sub.2                              O                                                   XVII                                                                                ##STR139##   185-187                                                                             C.sub.23 H.sub.27 N.sub.3 O.sub.2 Cl.sub.2.2HCl.H                             .sub.2 O                                             XVIII                                                                               ##STR140##   70    C.sub.26 H.sub.35 N.sub.3 O.sub.5                    IXX                                                                                 ##STR141##   74-76 C.sub.25 H.sub.33 N.sub.3 O.sub.2.2HCl.3H.sub.2                               O                                                    XX                                                                                  ##STR142##   88    C.sub.21 H.sub.27 N.sub.3 O.sub.2 S.0.5H.sub.2       __________________________________________________________________________                             O                                                

                  TABLE Ia                                                        ______________________________________                                        Example                                                                              Compound Name                                                          ______________________________________                                        IV     N-(4-chlorobenzoyl)-3,5,-bis(N-pyrrolidinylmethyl)-4-                         hydroxyaniline                                                         V      N-(4-methylbenzoyl)-3,5,-bis(N-pyrrolidinylmethyl)-4-                         hydroxyaniline                                                         VI     N-(2,4,dichorobenzoyl)-3,5,-bis(N-pyrrolidinylmethyl)-                        4-hydroxyaniline                                                       VII    N-(4-nitrobenzoyl)-3,5,-bis(N-pyrrolidinylmethyl)-4-                          hydroxyaniline                                                         VIII   N-(4-methoxybenzoyl)-3,5,-bis(N-pyrrolidinylmethyl)-4-                        hydroxyaniline                                                         IX     N-(3-trifluoromethylbenzoyl)-3,5,-bis(N-                                      pyrrolidinylmethyl)-4-hydroxyaniline                                   X      N-(2-chlorobenzoyl)-3,5,-bis(N-pyrrolidinylmethyl)-4-                         hydroxyaniline                                                         XI     N-(3-chlorobenzoyl)-3,5,-bis(N-pyrrolidinylmethyl)-4-                         hydroxyaniline                                                         XII    N-(2-trifluoromethylbenzoyl)-3,5,-bis(N-                                      pyrrolidinylmethyl)-4-hydroxyaniline                                   XIII   N-(4-trifluoromethylbenzoyl)-3,5,-bis(N-                                      pyrrolidinylmethyl)-4-hydroxyaniline                                   XIV    N-(2-methoxybenzoyl)-3,5,-bis(N-pyrrolidinylmethyl)-4-                        hydroxyaniline                                                         XV     N-(3-methylbenzoyl)-3,5,-bis(N-pyrrolidinylmethyl)-4-                         hydroxyaniline                                                         XVI    N-(2-methylbenzoyl)-3,5,-bis(N-pyrrolidinylmethyl)-4-                         hydroxyaniline                                                         XVII   N-(2,6,dichlorobenzoyl)-3,5,-bis(N-pyrrolidinyl-                              methyl)-4-hydroxyaniline                                               XVIII  N-(3,4,5,trimethoxybenzoyl)-3,5,-bis(N-                                       pyrrolidinylmethyl)-4-hydroxyaniline                                   IXX    N-(2,6,dimethylbenzoyl)-3,5,-bis(N-pyrrolidinylmethyl)-                       4-hydroxyaniline                                                       XX     N-(2-thiophenecarbonyl)-3,5-bis(N-pyrrolidinylmethyl)-                        4-hydroxyaniline                                                       ______________________________________                                    

EXAMPLE XXIN-(2-thiophenemethyl)carbonyl)-3,5,bis(N-pyrrolidinylmethyl)-4-hydroxyaniline

This example describes the synthesis of a compound having the formula##STR143## A solution having equimolar amounts of3,5-bis(N-pyrrolidinylmethyl)-4-hydroxyaniline, 2-thiopheneacetylchloride, and triethylamine in dioxane was stirred for 6 hours. Afterthe solvent was removed, the product was taken up in CHCl₃, washed withwater dried (MgSO₄), and the solvent removed. The oil afforded by thisprocedure was purified by MPLC (EtOAC/MeOH/NH₄ OH, 9:1:0.05) andcrystallized from EtOAc: mp 182° C. The IR and NMR spectra wereconsistent with the assigned structure and the elemental analysis wasconsistent with the empirical formula (C₂₂ H₂₉ N₃ O₂ S).

EXAMPLES XXII-XXVII EXAMPLE XXIIN-(benzoyl)-3,5-bis(pyrrolidinylmethyl)-4-hydroxybenzylamine

This example describes the synthesis of a compound having the formula##STR144## A solution having equimolar amounts of p-hydroxybenzylamine,benzoyl chloride, and triethylamine in dioxane was stirred for 6 hours.After the solvent was removed, the product was taken up in CHCl₃, washedwith water, dried (MgSO₄), and the solvent was purified by MPLC andcrystallized from EtOAc. The crystallized product was aminomethylated bymixing 6 g of the product, 6.5 ml of a 37% solution of formaldehyde, and4.5 ml of pyrrolidine in 3 ml of ethanol and stirring for 3 hours withwarming. The solvent was removed on a rotary evaporator, the product wasdissolved in CHCl₃, washed with water, dried (MgSO₄) and saturated withdry hydrogen chloride affording an oil. The solvent was removed andcrystallization was effected with isopropanol/ether, yielding off-whitecrystals: mp 94°-95° C. The IR and NMR spectra were consistent with theassigned structure and the elemental analysis was consistent with theempirical formula (C₂₄ H₃₁ N₃ O₂).

The additional compounds in Table II were prepared as above with theexception that the following aroyl chlorides were substituted forbenzoyl chloride. The IR and NMR spectra of each compound in Table IIwere consistent with the assigned structure and the elemental analyseswere consistent with the empirical formulae.

                  TABLE II                                                        ______________________________________                                                        M.P.                                                          Aroyl Chloride  (°C.)                                                                          Empirical Formula                                     ______________________________________                                        XXIII                                                                                ##STR145##   88-90   C.sub.24 H.sub.30 N.sub.3 O.sub.2 CL.2HCl.H.su                                b.2 O                                             XXIV                                                                                 ##STR146##   68      C.sub.25 H.sub.30 N.sub.3 O.sub.2 F.sub.3.2HCl                                .H.sub.2 O                                        XXV                                                                                  ##STR147##   187- 188                                                                              C.sub.25 H.sub.30 N.sub.3 O.sub.2 F.sub.3.2HCl    XXVI                                                                                 ##STR148##   90      C.sub.24 H.sub.30 N.sub.3 O.sub.2 Cl.2HCl.2H.s                                ub.2 O                                            XXVII                                                                                ##STR149##   205- 207                                                                              C.sub.24 H.sub.30 N.sub.3 O.sub.2 Cl.2HCl         ______________________________________                                    

                  TABLE IIa                                                       ______________________________________                                        Example     Compound Name                                                     ______________________________________                                        XXIII       N-(4-chlorobenzoyl)-3,5-bis(pyrrolidinylmethyl)-4-                            hydroxybenzylamine                                                XXIV        N-(2-trifluoromethylbenzoyl)-3,5-bis(pyrrolidinyl-                            methyl)-4-hydroxybenzylamine                                      XXV         N-(3-trifluoromethylbenzoyl)-3,5-bis(pyrrolidinyl-                            methyl)-4-hydroxybenzylamine                                      XXVI        N-(2-chlorobenzoyl)-3,5-bis(pyrrolidinylmethyl)-4-                            hydroxybenzylamine                                                XXVII       N-(3-chlorobenzoyl)-3,5-bis(pyrrolidinylmethyl)-4-                            hydroxybenzylamine                                                ______________________________________                                    

EXAMPLE XXVIIIN-(4-aminobenzoyl)-3,5-bis(pyrrolidinylmethyl)-4-hydroxyaniline

This example describes the synthesis of a compound having the formula##STR150## A solution having equipmolar amounts of3,5-bis(N-pyrrolidinylmethyl)-4-hydroxyaniline, p-nitrobenzoyl chloride,and triethylamine in dioxane was stirred for 6 hours. After the solventwas removed, the product was taken up in CHCl₃, washed with water, dried(MgSO₄), and the solvent removed. The oil afforded by this procedure waspurified by MPLC (EtOAc/MeOH/NH₄ O₄, 9:1:0.05) and crystallized fromEtOAc yielding a product having a m.p. of 158°-159° C. and an elementalanalysis consistent with the empirical formula of C₂₃ H₂₈ N₄ O₄. Thisproduct was then hydrogenated (Pd/C, EtoH) to yield the compound havinga m.p. of 88°-90° C. The IR and NMR spectra were consistent with theassigned structure and the elemental analysis was consistent with theempirical formula (C₂₃ H₃₀ N₄ O₂).

EXAMPLE XXIX 3,5-bis(N-pyrrolidinylmethyl)-4-hydroxyacetanilide

This example describes the synthesis of a compound having the formula##STR151## A mixture of 4 grams 4-acetamidophenol, 6.5 ml of a 37%solution of formaldehyde and 4.5 ml of pyrrolidine in 3 ml of ethanolwas stirred with warming for 3 hours. The solvent was removed on arotary evaporator, dissolved in CHCl₃, wased with water, dried (MgSO₄)and saturated with dry hydrogen chloride. The solvent was removed andcrystallization was effected with isopropanol/ether yielding whitecrystals: mp 73°-76° C. The IR and NMR spectra were consistent with theassigned structure and the elemental analysis was consistent with theempirical formula (C₁₈ H₂₇ N₃ O₂.2.4HCl.0.5H₂ O).

EXAMPLE XXX 3,5-bis(N-pyrrolidinylmethyl)-4-hydroxyaniline

This example describes the synthesis of a compound having the formula##STR152##

A solution of 100.0 g (0.315 mol) of the compound prepared in ExampleXXIX in 200 ml of 6M HCl was heated to reflux for 3 hours. The solutionwas basified with solid KOH to a pH of 11. The resulting solid wascollected by filtration and washed with water and cold ether.Crystallization from ether yielded pale yellow needles: mp 100°-105° C.The HCl salt formed white crystals: mp 219°-221° C. The IR and NMRspectra were consistent with the assigned structure and the elementalanalysis was consistent with the empirical formula (C₁₆ H₂₅ N₃ O).

EXAMPLE XXXI N-(benzoyl)3,5-bis(morpholinomethyl)-4-hydroxyaniline

This example describes the synthesis of a compound having the formula##STR153## This compound was prepared as was the compound of Example IIIwith the exception that morpholine was substituted for pyrrolidineyielding white crystals: mp 152°-154° C. The IR and NMR spectra wereconsistent with the assigned structure and the elemental analysis wasconsistent with the empirical formula (C₂₃ H₂₉ N₃ O₄.2.HCl.1.75H₂ O).

EXAMPLE XXXII N-(benzoyl)3,5-bis(piperidinylmethyl)-4-hydroxyaniline

This example describes the synthesis of a compound having the formula##STR154## This compound was prepared as was the compound of Example IIIwith the exception that piperidine was substituted for pyrrolidineyielding white crystals: mp 138°-140° C. The IR and spectra wereconsistent with the assigned structure and the elemental analysis wasconsistent with the empirical formula (C₂₅ H₃₃ N₃ O₂.2HCl.2H₂ O).

EXAMPLE XXXIII N-([3,5-bis(pyrrolidinylmethyl)-4-hydroxy]benzoyl)aniline

This example describes the synthesis of a compound having the formula##STR155## Following the method by Corey and Venkateswarlu J. Amer.Chem. Soc 94, 6190 (1972) for protecting alcohols and carboxylic acids,19.7 g (0.290 mole) of imidazole was added to a solution of 10 g (0.072mole) of p-hydroxybenzoic acid and 22.9 g (0.152 mole) oftert-butyldimethylsilylchloride in 20 ml of DMF. The solution was heatedat 50°-60° C. for 5 hours, after which it was poured into H₂ O andextracted with CH₂ Cl₂. The organic phase was washed with a saturatedsolution of NaHCO₃ and dried over MgSO₄. The solvent was removed underreduced pressure to give a clear, colorless oil which solidified uponstanding.

Using Wissner's J. Org. Chem. 43, 3972 (1978) procedure for preparingcarboxylic acid chloride under neutral conditions, the crude product wasdissolved in 26 ml of CH₂ Cl₂ containing 12 drops of DMF. The solutionwas cooled at 0° C. and to this was added 4.1 ml (0.049 mole) of oxalylchloride. The solution was stirred for 1.5 hours at 0° C. and for 40hours at room temperature. The solvent was stripped off, leaving an oil.This acid chloride was used immediately without further purification.

A solution of the crude acid chloride and 3.4 ml of (0.042 mole) ofpyridine in CH₂ Cl₂ was cooled to 0° C.-15° C. To this solution wasadded 3.2 ml (0.035 mole) of aniline, maintaining the temperature below20° C. After stirring the solution for 2.5 hours at room temperature,the solvent was stripped off giving a mixture of orange oil and whitesolids. The residue was dissolved in H₂ O and extracted with CH₂ Cl₂.The combined extracts were dried over MgSO₄ and filtered. Afterstripping off the solvent under reduced pressure, an orange solid wasobtained.

As described in Corey and Venkateswarlu's procedure for cleaving off thetert-butyldimethylsilyl group, the orange solid was treated with 70 mlof 1M solution of N-Bu₄ N⁺ F⁻ in THF (0.07 mole F⁻) for 5 minutes at 0°C. and for 45 minutes at 25° C. After quenching the reaction with H₂ O,the aqueous mixture was extracted with CH₂ Cl₂. The CH₂ CL₂ extractswere dried over MgSO₄ and filtered. After stripping off the solvent, 6.5g (87%) of p-hydroxybenzanilide was obtained.

A mixture of 6.5 (0.031 mole) of the p-hydroxybenzanilide, 5.1 ml (0.067mole) of pyrrolidine in 100 ml of ethanol was refluxed for 11 hours.After the reaction was complete, the solvent was removed on a rotaryevaporator giving a yellow residual oil. Purification by medium pressureliquid chromatography on silica gel (ETOAC/MeOH/NH₄ OH, 4:1:0.01) andrecrystallization from ETOAC afforded 2.25 g (19%) of white solids: mp154.5°-155.5° C. The HCl salt was made by dissolving 1.85 g (0.0049mole) of the free base in CH₂ Cl₂ -ether and bubbling HCl gas into thesolution. After removal of the solvent, 2.50 g of white solids wereobtained: mp 88°-90° C. The IR and NMR spectra were consistent with theassigned structure and the elemental analysis was consistent with theempirical formula (C₂₃ H₂₉ N₃ O₂.2HCl.11/4H₂ O).

EXAMPLE XXXIV(N-benzoyl)-N-(methyl)-3,5-bis(pyrrolidinylmethyl)-4-hydroxyaniline

This example describes the synthesis of a compound having the formula##STR156## A mixture of 10 g (0.073 mole) of p-methoxyanisidine and 90ml (0.80 mole) of HBr (48% aqueous solution) was refluxed for 6 hours.Excess HBr was removed on a rotary evaporator leaving a gray,crystalline solid residue. After neutralization with conc. NH₄ OH, theaqueous solution was extracted and filtered. Removal of the solventunder reduced pressure afforded a solid residue.

Protection of the hydroxyl group with tert-butyldimethylsilyl group wasaccomplished in Example XXXIII above.

Next, to a cooled solution (-10° C. to 0° C.) of 7.0 g (0.029 mole) ofthe protected-phenolic product in 50 ml of dioxane was added 20.2 ml(0.145 mole) of triethylamine and 4.1 g (0.029 mole) of benzoylchloride. The mixture was allowed to warm to room temperature andstirred for 18 hours. White precipitates of Et₃ N.HCl were filtered off,and the filtrate was stripped off to give a dark oil which was taken upin ether and washed successively with H₂ O, saturated NaHCO₃ solutionand brine. The ethereal phase was dried over MgSO₄, and removed in arotary evaporator to give an oily residue.

The tert-butyldimethylsilyl group was cleaved off by n-Bu₄ N⁺ F⁻ in THFas described in Example XXXIII.

Aminomethylation was achieved by refluxing the deprotected intermediatewith 4.8 ml (0.064 mole) of formaldehyde (37% solution) and 5.3 ml(0.064 mole) of pyrrolidine in 100 ml ethanol for 11 hours. Aftercompletion of the reaction, the solvent was stripped off under reducedpressure, giving a dark oil. The oil was purified by medium-pressureliquid chromatography on silica gel (EtoAC/MeOH/NH₄ OH, 4:1.0:0.01) togive off-white crystal solids. The HCl salt was made by dissolving thefree amine in ether and bubbling HCl gas into the solution: mp 63°-65°C. The IR and NMR spectra were consistent with the assigned structureand the elemental analysis was consistent with the empirical formula(C₂₄ H₃₁ N₃ O₂.2HCl.23/4H₂ O).

EXAMPLE XXXVN-(4-trifluoromethyl)-3,5-bis(pyrrolidinylmethyl)-4-hydroxybenzylamine

This example describes the synthesis of a compound having the formula##STR157## This compound was prepared as was the compound of ExampleXXII with the exception that 4-trifluoromethylbenzoyl chloride wassubstituted for benzoyl chloride yielding white crystals: mp 85°-87° C.The IR and NMR spectra were consistent with the assigned structure andthe elemental analysis was consistent with the empirical formula (C₂₅ H₃ON₃ O₂ F₃.2HCl.H₂ O).

EXAMPLE XXXVI 2,6-bis(pyrrolidinylmethyl)-4-benzyl-phenol

This example describes the synthesis of a compound having the formula##STR158## The aminomethylation of 4-hydroxydiphenylmethane was carriedout as p-benzyloxyphenol of Example I affording an oil. Purification byMPLC (EtOAc/MeOH/NH₄ OH 4:1:0.05) on silica gel afforded a clear viscousoil. Crystallization from isopropanol yielded white crystals: mp196°-198° C. The IR and NMR spectra were consistent with the assignedstructure and the elemental analysis was consistent with the empiricalformula (C₂₅ H₂₈ N₅ Cl).

EXAMPLE XXXVII

The following examples describe the pharmacological evaluation of thecompounds made in accordance with the present invention. In particular,these examples describe the evaluation of antiarrhythmic activity bycoronary ligation in the well known Harris dog model. Ventriculararrhythmias were induced in adult mongrel dogs (10-15 kg) of either sexby two-stage ligation of the left anterior descending coronary artery.On the following day a high percentage of (90-100%) of ectopic beatsexisted. The test compound in saline was infused intravenously at acumulative rate of 0.3 to 1.2 mg/kg/min (base) until normal sinus rhythmor toxicity occurred. Normal sinus rhythm was defined as 90-100% normalcomplexes over a 5 min period. The results of these tests are set forthin Table III.

EXAMPLE XXXVIII

The following examples describe the in vitro evaluation ofanticholinergic activity in the isolated guinea pig ileum. Fasted, maleHartley guinea pigs (300-400 g) were killed by a blow to the head. A 1cm segment of ileum was removed and placed in a bath containingphysiological saline solution (in mmol/L: NaCl, 120; NaHCO₃, 25; KCl,4.7; MgSO₄, 0.57; KH₂ PO₄, 1.2; CaCl₂, 1.96; dextrose, 11.1). One end ofthe ileal strip was impaled onto a platinum wire electrode; and theother end was tied to a stationary glass rod. Basal tension was set at0.1-0.3 g and peak developed tension in response to field stimulation(100-150 V, 10 msec pulse duration, 0.2 Hz) was measured with a tensiontransducer. Tension development was then assessed after test drug was ata concentration of 4 mg/L. Since contractile tension in this preparationis due to cholinergic activity, the percent inhibition was termed theanticholinergic activity of the drug; the greater the percent inhibitionthe greater the anticholinergic activity. The results of these tests areset forth in Table III.

EXAMPLE XXXIX

The following example describes the in vitro evaluation of negativeinotropic activity in the cat papillary muscle. The heart ofanesthetized cats (1-3 Kg) was removed through a left thoracotomy andplaced into a bath containing physiological saline solution (inmmoles/L: NaCl, 128; KCl, 4.0; NaHCO₃, 20; KH₂ Po4, 1.8; CaCl₂, 2.5;MgCl₂, 0.5; dextrose 5.5) having a pH of 7.4, at room temperature.Thereafter the heart was transferred to a dissecting dish containingphysiological saline at 35° C. and bubbled with 95% O₂ /5% CO₂, wherethe atrial tissue was removed and discarded. The papillary muscle wasremoved from the heart after in situ measurement of its diameter; theapical and tedinous ends of the muscle were tied to the stationary glasshook of a platinum field-stimulation electrode with 4-0, 5-0, or 6-0silk or nylon suture. The stimulating electrode and attached muscle werecarefully transferred into 30 ml bath containing physiological saline at35° C. bubble with 95% O₂ /5% CO₂, pH 7.4. The suture previously tied tothe tendinous end of the muscle was then attached to the outer hook oftension transducer where the muscle was gently stretched to the peak ofits length-tension curve (L_(max)) while being stimulated by constantcurrent pulses just above threshold intensity with a duration of 5 msecand a frequency of 0.2 Hz. The muscle was equilibrated at L_(max) withjust above threshold intensity pulses for 90-120 minutes. The testcompound was administered at 4 mg/ml to determine the percent inhibitionof tension development.

EXAMPLE XL

The following examples describe the pharmacological evaluation of thecompounds in accordance with the present invention. In particular, theseexamples describe the evaluation of antiarrhythmic activity in theOubain dog model. Ventricular arrhythmias were induced in dogs byintravenous administration of oubain until sustained ventriculartachycardia was present (greater than 95% ectopic beats) for 10 minutes.The test compound was infused intravenously in saline at a rate of about0.3 to about 5 mg/kg/min until normal sinus rhythm or toxicity occurred.Normal sinus rhythm was defined as 90-100% normal complexes over a 5minute period. The results of these tests are set forth in Table III.

                  TABLE III                                                       ______________________________________                                                                         Anticholinergic                                       Anti-                   Inhibition                                            arrhythmic  Anti-       of Guinea                                    Compound ED.sup.1 in arrhythmic ED.sup.1                                                                       Pig Ileum                                    (Example Harris Dog  in Ouabain Dog                                                                            (% inhibition                                No.)     (mg/kg IV)  (mg/kg IV)  at 4 mg/L)                                   ______________________________________                                        I        4.5         1.5         62                                           II       11          1.9         9                                            III      5           3.4         35                                           IV       7           1.5         49                                           V        15          3           22                                           VI       --          low activity                                                                              11                                           VII      --          11          24                                           VIII     --          7.2         24                                           IX       --          2.25        62                                           X        --          5.8         0                                            XI       --          3.75        37                                           XII      --          6.2         0                                            XIII     9.0         5.25        43                                           XIV      --          3.0         31                                           XV       --          5.3         32                                           XVI      --          2.0         9.4                                          XVII     --          2.0         14.3                                         XVIII    --          inactive.sup.2                                                                            5.9                                          IXX      --          4.3         15                                           XX       --          1.9         4                                            XXI      --          low activity                                                                              13                                           XXII     --          3.0         32                                           XXIII    --          3.8         56                                           XXIV     --          1.7         8.5                                          XXV      --          5.5         72                                           XXVI     --          2.3         18                                           XXVII    --          9.8         78                                           XXVIII   --          4.5         0                                            XXIX     inactive.sup.2                                                                            --          --                                           XXX      inactive.sup.2                                                                            --          3                                            XXXI     --          16.5        37                                           XXXII    --          11          33                                           XXXIII   --          3.5         --                                           XXXIV    --          16          16                                           XXXV     --          4.5         49                                           XXXVI    low activity                                                                              --          14                                           Quinidine                                                                              10.1        --          62                                           Disopyramide                                                                            6.8        4.4         81                                           Changrolin                                                                             10.3        5.5         43                                           ______________________________________                                         .sup.1 ED is the effective dose required to sustain normal sinus rhythm.      .sup.2 No effect on sinus rhythm up to a cumulative dose of 30 mg per kg.

EXAMPLE XLI

The compounds listed in Table IV were prepared by one of the threedifferent methods described. The method employed for individualcompounds is designated in Table IV.

Synthetic Method A

Due to the commercial availability of the appropriate4-hydroxybenzoates, compounds 1, 2-15, 24, 26 and 27 were prepared inone step. A typical example is the aminomethylation of methyl4-hydroxybenzoate to yield compound 1.

To a solution of 0.10-0.14 moles of methyl 4-hydroxybenzoate was added,in one lot, a combination of 0.22-0.31 moles pyrrolidine and 0.30-0.42moles 37% aqueous formal dehyde solution which was premixed at ice-bathtemperature. This reaction mixture was stirred at reflux for 16-20hours. The mixture was concentrated under reduced pressure to afford anoil which was partitioned between water and ethyl acetate. The organiclayer was dried (MgSO₄) and filtered. This filtrate was concentratedunder reduce pressure to give an oil which was dissolved in ether andtreated with HCL (g) until acidic. The precipitated dihydrochloride saltwas collected by filtration and crystallized from methanol/ether.

Synthetic Method B

Compounds 16-22 was prepared by reacting a volatile, acid-stable alcoholwith the appropriate carboxylic acid and HCl as described below forcompound 17.

A solution of 0.08-0.12 moles of 3-(4'-hydroxyphenyl)propanoic acid in300-500 ml of ethanol was saturated with HCl (g). This mixture wasstirred at reflux for 16-20 hours. Volatiles were removed under reducedpressure to yield the product oil, ethyl3-(4'-hydrroxyphenyl)propanoate.

The ester obtained was reacted with pyrrolidine and formaldehyde asdescribed in Synthetic Method A to yield compound 17.

Synthetic Method C

Esters of non-volatile or acid-unstable alcohols were prepared in amanner analogous to that described below for compound 25.

A suspension of 7.0-7.4 moles 4-hydroxybenzoic acid in 18.8-19.2 molesof acetic anhydride is stirred over a steam bath. On addition of acatalytic amount (0.5-1.5 ml) of concentrated sulfuric acid rapiddissolution of the 4-hydroxybenzoic acid occurred and was followedimmediately by precipitation of product. This mixture was warmed by thesteam bath an additional 30-60 minutes then cooled to room temperature.The slurry obtained was filtered and the filter cake was washed withwater. The white solid obtained in this manner was 4-acetoxybenzoic acidand was used without further purification.

A mixture of the above product and thionyl chloride (1:6 ratio) wasstirred at reflux for 16-18 hours. All volatiles were then removed underreduced pressure to give 4-acetoxybenzoyl chloride, a beige solid whichwas used without further purification.

To a stirred solution of 0.2-0.3 moles of acid chloride in 40-50 ml ofCHCl₃ was added 0.2-0.3 moles of cyclohexylmethanol. The reactionmixture was stirred at reflux for 16-20 hours. Volatiles were removedunder reduced pressure to give an oil which was treated with hexanes.Any insoluble material was removed by filtration and the filtrate wasconcentrated to give the oil, cyclohexylmethyl 4-acetoxybenzoate.

The above oil was dissolved in methanol and treated with HCL (g) for5-10 minutes. After removal of volatiles, the remaining oil,cyclohexylmethyl 4-hydroxybenzoate was converted to compound 27 in afashion analogous to that described in Synthetic Method A.

                                      TABLE IV                                    __________________________________________________________________________     ##STR159##                                                                                                      IN VIVO.sup.b                                                     IN VITRO.sup.a                                                                            Mean E.D.                                                    Synthetic                                                                          # Tissues                                                                           Mean E.D.                                                                           Bolus Ins.                                                                          Duration of Action-Recovery Time                                              (Minutes)                            Compound                                                                            R           Method                                                                             Converted                                                                           (ug/mL)                                                                             (MPK) 50%    80%    100%                   __________________________________________________________________________    1     CH.sub.3 O.sub.2 C                                                                        A    2/6   23.00 2.5                                        2     HO.sub.2 C  A    0/7   --    N.C.                                       3     CH.sub.3 CH.sub.2 O.sub.2 C                                                               A    7/7   23.00 2.5                                        4     PhO.sub.2 C A    --    --    N.C.                                       5     (CH.sub.3).sub.2 CHO.sub.2 C                                                              A    3/3   11.43                                            6     CH.sub.3 (CH.sub.2).sub.2 O.sub.2 C                                                       A    3/3   6.60                                             7     CH.sub.3 CH.sub.2 CH(CH.sub.3)O.sub.2 C                                                   A    2/2   6.70                                             8     CH.sub.3 (CH.sub.2).sub.6 O.sub.2 C                                                       A    2/2   2.00                                             9     CH.sub.3 (CH.sub.2).sub.7 O.sub.2 C                                                       A    1/3   5.00                                             10    (CH.sub.3).sub.2 CHCH.sub.2 O.sub.2 C                                                     A    5/5   3.80   1.75 5      20     45                     11    CH.sub.3 (CH.sub.2).sub.3 O.sub.2 C                                                       A    3/3   2.30                                             12    CH.sub.3 (CH.sub.2).sub.5 O.sub.2 C                                                       A    3/4   3.46                                             13    CH.sub.3 (CH.sub.2).sub.4 O.sub.2 C                                                       A    2/2   3.50                                             14    PhCH.sub.2 O.sub.2 C                                                                      A    3/5   2.40                                             15    CH.sub.3 (CH.sub.2).sub.8 O.sub.2 C                                                       A    2/6   3.00                                             16    CH.sub.3 CH.sub.2 O.sub.2 CCH.sub.2                                                       B    3/3   16.50                                            17    CH.sub.3 CH.sub.2 O.sub.2 CCH.sub.2 CH.sub.2                                              B    3/3   15.90                                            18    CH.sub.3 O.sub.2 CCH.sub.2 CH.sub.2                                                       B    4/4   23.00                                            19    FCH.sub.2 CH.sub.2 O.sub.2 C                                                              B    2/3   21.00                                             20                                                                                  ##STR160##  B    4/4   71.20                                                                               30.0                                      21    CH.sub.3 O.sub.2 CCH.sub.2                                                                B    1/4   93.50                                            22    CH.sub.2CHCH.sub.2                                                                        B    3/4   2.67                                             23    (CH.sub.3).sub.2 CHCH.sub.2 NHCO                                                          A    2/4   12.40                                            24    CH.sub.3 (CH.sub.2).sub.11 O.sub.2 C                                                      C    2/5   3.00                                             25                                                                                   ##STR161## C    4/5   1.33                                             26    (CH.sub.3).sub.2 CHCH.sub.2 CH.sub.2 O.sub.2 C                                            A    5/5   .88                                              27                                                                                   ##STR162## A    2/5   1.50                                             28                                                                                   ##STR163## C    3/4   17.20                                            __________________________________________________________________________     NOTES                                                                         .sup.a IN VITRO studies involved acetylstrophanthidininduced arrhythmias      in Guinea Pig right atria.                                                    .sup.b IN VIVO studies involved Ouabain dog model. Duration of action         based on monitoring prolongation of QRS.                                      N.C. -- no conversion                                                    

The following test procedure was used to assess antiarrhythmic activitysince the contractions elicited by the SA node of the guinea pig rightatrium can be made arrhythmic by the means of anacetylstrophanthidin-induced arrhythmia with the accepted arrhythmogenicconcentration (30 λ of 5 mg/ml stock in a 30 ml organ bath). Conversionof the arrhythmia with incremental doses will give an effective dose(ED) which can be used to rank the activity of these compounds. Theprocedure is a modification of the procedures described by R. G. Burneyet al., American Heart Journal, Vol. 88, No. 6, 765 (1974) and M. J.Peach et al., Journal of Pharmacol. Exp. Therapeutics, Vol. 183, 73(1972), the primary difference being that in the present procedure, anarrhythmia is created and then reversed whereas in the publishedprocedures, the tissue is pretreated with antiarrhythmic and then anattempt is made to induce an arrhythmia.

The guinea pig's right atria is isolated and a platinum hook and goldchain are attached to the shoulder part of the atria while a stationaryglass rod and hook are attached at the apex. One hour of equilibrationis allowed with a wash every 20 minutes.

Acetylstophanthidin is administered (30 λ of a stock 5 mg/ml in absolute100% ethanol) and the atria is set aside for one hour to allowarrhythmia to develop. Once sustained arrhythmia is present, anantiarrhythmic drug may be screened in incremental doses atpredetermined times.

After an arrhythmia is converted to normal sinus rhythm (NSR), it shouldbe noted that the cumulative dose is the ED.

The present invention has been described in detail and with particularreference to the preferred embodiments; however, it will be understoodby one having ordinary skill in the art that changes can be made theretowithout departing from the spirit and scope thereof.

What is claimed is:
 1. A compound of the formula ##STR164## wherein X is##STR165## wherein R₁ is phenyl, benzyl, cinnamoyl, thiophene, furan,pyrrole, imidazole, pyrazole, oxazole or thiazole; W is hydrogen orhydroxy; (Y)_(A) is positioned ortho to W and is an aminoloweralkylhaving the formula --CH₂ NR₂ R₃ where R₂ and R₃ are the same ordifferent and may be lower alkyl or R₂ and R₃ may together with N form apyrrolidine, piperidine or azepine ring, and A is 2; n and m areindependently from 0 to 5; and R is straight or branched C₁ -C₁₀ alkyl,C₃ -C₁₀ cycloalkyl, straight or branched C₂ -C₄ alkenyl, or straight orbranched C₂ -C₄ alkynyl, or a pharmaceutically acceptable salt thereof.2. A compound of claim 1 wherein X is ##STR166## W is hydroxy, (Y)_(A)is positioned ortho to W and is an aminoloweralkyl having the formula--CH₂ NR₂ R₃ where R₂ and R₃ together with N form a pyrrolidine orpiperidine ring, n and m are each 0 to 5, and R is a straight orbranched C₁ -C₆ alkyl.
 3. A compound of claim 2 wherein R₁ and R₃together with N form a pyrrolidine ring.
 4. A compound of claim 3wherein X is ##STR167##
 5. A compound of claim 4 wherein n is 0, 1 or 2,m is 2, and R is methyl, ethyl or cyclopropyl.
 6. A compound of claim 5wherein n is 1, m is 0, and R is cyclopropyl.
 7. A compound of claim 5wherein n is 1, m is 2, and R is methyl.
 8. A compound of claim 5wherein n is 0, m is 2, and R is methyl.
 9. A cardiac arrhythmiccomposition containing an antiarrhythmic-effective amount of thecompound having the formula ##STR168## wherein X is ##STR169## whereinR₁ is phenyl, or benzyl, cinnamoyl, thiophene, furan, pyrrole,imidazole, pyrazole, oxazole or thiazol; W is hydrogen or hydroxy;(Y)_(A) is positioned ortho to W and is an aminoalkyl having the formula--CH₂ NR₂ R₃ wherein R₂ and R₃ are the same or different and may belower alkyl or R₂ and R₃ may together with N form a pyrrolidine,piperidine or azepine ring, and A is 2; n and m are independently from 0to 5; and R is straight or branched C₁ -C₁₀ alkyl, C₃ -C₁₀ cycloalkyl,straight or branched C₂ -C₄ alkenyl, straight or branched C₂ -C₄alkynyl, or a pharmaceutically acceptable salt thereof; in admixturewith a pharmaceutically acceptable carrier or diluent.
 10. Thecomposition of claim 9 wherein X is ##STR170## W is hydroxy, (Y)_(A) ispositioned ortho to W and is an aminoloweralkyl having the formula --CH₂NR₂ R₃ where R₂ and R₃ together with N form a pyrrolidine or piperidinering, n and m are each 0 to 5, and R is a straight or branched C₁ -C₆alkyl.
 11. The composition of claim 10 wherein R₁ and R₃ together with Nform a pyrrolidine ring.
 12. The composition of claim 11 wherein X is##STR171##
 13. The composition of claim 4 wherein n is 0, 1 or 2, m is2, and R is methyl, ethyl or cyclopropyl.
 14. A method of treatingcardiac arrhythmias in a patient by administration of an antiarrhythmiceffective amount to such patient of a compound of the formula ##STR172##wherein X is ##STR173## wherein R₁ is phenyl, or benzyl cinnamoyl,thiophene, furan, pyrrole, imidazole, pyrazole, oxazole or thiazole; Wis hydrogen or hydroxy; (Y)_(A) is positioned ortho to W and is anaminoloweralkyl having the formula --CH₂ NR₂ R₃ where R₂ and R₃ are thesame or different and may be lower alkyl or R₂ and R₃ may together withN form a pyrrolidine, piperidine or azepine ring, and A is 2; n and mare independently from 0 to 5; and R is straight or branched C₁ -C₁₀alkyl, C₃ -C₁₀ cycloalkyl, straight or branched C₂ -C₄ alkynyl, or apharmaceutically acceptable salt thereof.
 15. The method of claim 14wherein X is ##STR174## W is hydroxy, (Y)_(A) is positioned ortho to Wand is an aminoloweralkyl having the formula --CH₂ NR₂ R₃ where R₂ andR₃ together with N form a pyrrolidine or piperidine ring, n and m areeach 0 to 5, and R is a straight or branched C₁ -C₆ alkyl.
 16. Themethod of claim 15 wherein R₁ and R₃ together with N form a pyrrolidinering.
 17. The method of claim 16 wherein X is ##STR175##
 18. The methodof claim 17 wherein n is 0, 1 or 2, m is 2, and R is methyl, ethyl orcyclopropyl.
 19. The method of claim 18 wherein n is 1, m is 0, and R iscyclopropyl.